Solid-phase synthesis protocols as described by Merrifield are well-known in the art for synthesizing peptides. A number of different resin supports have been adopted as standards in the field. Besides the original chloromethylated polystyrene of Merrifield, benzhydrylamine type resins have been widely used to prepare peptide amides (Stewart, Solid Phase Peptide Synthesis, Pierce Chemical Co., Rockford, IL (1984), Pietta et al, J. Chem. Soc. D..:650-651 (1970); Orlowski et al, J. Org. Chem., 50:3701-5 (1976); Matsueda et al, Peptides, 2:45-50 (1981) and Tam, J. Org. Chem., 50:5291-8 (1985)). These solid phases are acid labile (Albericio et al, Int. J. Peptide Research. 30:206-216 (1987)).
In recent years acid labile resins using a trialkoxydiphenyl-methylester moiety have become popular due to their ease of use for peptide synthesis with FMOC protected amino acids (Rink, Tetrahedron Letters, 28:3787-90 (1987); U.S. Pat. No. 4,859,736; and U.S. Pat. No. 5,004,781). The peptide is eventually released by cleavage with trifluoroacetic acid. This resin which is used to attach blocked amino acids for the purposes of peptide synthesis of peptides, has the following structure: ##STR1## This structure is part of an insoluble polymer which will permit easy separation from liquid reactants by simple physical separations such as filtration, centrifugation, sedimentation and decanting, etc.
Rink synthesized the compound by reacting resorcinol diether with p-hydroxybenzoyl chloride in the presence of the Lewis acid aluminum chloride to give 2,4-dimethyl-4'hydroxybenzophenone. This product was suspended in ethanol and cesium hydroxide monohydrate wa added. After being allowed to react, the reaction product was lyophilized. This material was then reacted with chloromethyl-polystyrene-1% divinylbenzene, dried and suspended in pyridine three times, dried and dissolved in DMF. The ketone formed was reduced and used for peptide synthesis. The method for preparing this resin uses cesium salts and involves several chemical purification steps which are time consuming and expensive.
Using the solid phase technique during peptide synthesis has become a standard for peptide synthesis as is discussed in the Rink patents (U.S. Pat. Nos. 4,859,736 and 5,004,781), the contents of which are hereby incorporated by reference. However, the use of multistep solid phase techniques to synthesize the Rink-type solid phase itself, prior to reaction to form a peptide or ester bond, has not been achieved prior to the present invention described herein.